1. Field of the Invention
a. The present invention relates to a pharmaceutical composition having improved solubility, which includes lipid nanoparticles comprised of a lipid mixture of phospholipid, cholesterol and ionic lipid; and a tricyclic derivative compound, and to a method for preparing the lipid nanoparticles.
2. Description of the Related Art
Korean Patent Registration No. 10-0667464-0000 discloses a tricyclic derivative compound of Formula 1 as shown below. The compound of Formula 1 that is a colchicine derivative exhibits a very strong cytotoxicity against cancer cell lines, shows a significantly reduced toxicity compared to a colchicine or taxol injection in an animal toxicity test, significantly reduces the tumor size and weight, and shows strong angiogenesis inhibitory activity in HUVEC cells. Thus, the compound of Formula 1 is clinically useful as an anticancer agent, a proliferation inhibitor and an angiogenesis inhibitor. However, the tricyclic derivative compound of Formula 1 has a very low solubility in an aqueous phase, and thus has low bioavailability in an aqueous phase for drug preparation, such as sterile water, water for injection, deionized water or a buffer solvent or is released in body fluids and tissues immediately after administration in vivo even when it is administered as a solubilized pharmaceutical composition. For this reason, the development of a stable pharmaceutical formulation including the compound of Formula 1 has been limited.
In order to solubilize the tricyclic derivative compound of Formula 1 in an aqueous phase, solubilizing agents such as dimethyl sulfoxide, Tween 80 or cremophor should be used. These solubilizing agents, particularly cremophor, are known to cause serious allergic reactions as side effects on the human body.

There have been disclosed various technologies for solubilizing drugs having low solubility, including nanoparticles, solid dispersions and micelles.
When insoluble hydrolysable compounds are incorporated into lipid aggregates such as liposomes or micelles, the compounds can be administered under clinical conditions. Liposomes are known as biodegradable delivery systems which are physiologically compatible with a wide range of drugs. In addition, because liposomes eliminate the need for solubilization in an aqueous phase, an insoluble compound can be more concentrated than a single free state and can be easily formulated in liposomes, and thus the drug can be delivered to a target site at high concentration.
U.S. Pat. Nos. 5,439,686 and 5,560,933 disclose the preparation of formulations in which paclitaxel is stably dispersed with albumin microparticles. However, these formulations have a problem in that the effect of paclitaxel is reduced due to the adsorption of serum albumin of the paclitaxel-loaded albumin as compared to conventional formulations prepared using surfactants.
Moreover, Korean Patent Laid-Open Publication No. 1999-0069033 discloses a technology of solubilizing a diterpenoid alkaloid drug using an amphiphilic block copolymer including polylactide or polyglycolide as a biodegradable hydrophobic polymer and polyethylene glycol as a hydrophilic polymer. This technology is effective for drug solubilization and a decrease in the toxicity of the solubilized formulation, but has a shortcoming in that, because the structure of micelles is unstable upon administration in vivo, the core-micelle shell structure is easily broken so that the encapsulated drug is released.
In addition, Korean Patent Laid-Open Publication No. 2001-0030599 discloses a formulation including camptothecin encapsulated in liposome and a preparation method thereof. The formulation includes one or more liposomes including phospholipid and camptothecin, and this liposome formulation has improved pharmacokinetics and stability. However, the technology of encapsulating a drug in liposomes is not suitable for the preparation of a high-concentration drug solution, because the amount of the drug encapsulated in unit liposome is small.
As described above, for the development of a pharmaceutical formulation in which the tricyclic derivative compound of Formula 1, which has low solubility in an aqueous medium, is solubilized at high concentration, there is an urgent demand for a technology that enables the tricyclic derivative compound to be stably contained in structures and allows the compound-containing structures to be stably dispersed in an aqueous phase, thereby solubilizing the poorly soluble drug in the aqueous phase. In addition, there is a need for the development of nanostructures for solubilization of the tricyclic derivative compound, in which the nanostructures have excellent in vivo stability so that they are not easily broken by in vivo components, including body fluids, proteins and salts, upon administration in vivo, and thus the drug is not librated or released from the nanostructures after administration in vivo.
Accordingly, the present inventors have found that, when lipid nanoparticles are prepared by introducing a lipid mixture to a poorly tricyclic derivative compound, the solubility of the tricyclic derivative compound is improved without having to use a solubilizing agent harmful to the human body, and the improved solubility is maintained even when water is added to the lipid nanoparticles in order to form an injectable formulation, and also the prepared solid-state lipid nanoparticles have long-term storage stability, thereby completing the present invention.
Throughout this application, several patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications is incorporated into this application in order to more fully describe this invention and the state of the art to which this invention pertains.